The blood vessels that vascularize the central nervous system exhibit unique properties which control the flow of cells, ions, and molecules from plasma to the brain. Referred to as the blood-brain barrier, it is vital for the protection of the brain and maintains homeostasis. Dysfunction of the blood-brain barrier is linked with a range of neurological conditions.
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The circulatory system and microvasculature
Blood is carried from the heart to organs and tissue throughout the body via systems of blood vessels. Vessels deliver nutrients and oxygen, whilst removing waste products and carbon dioxide and regulating how the immune system interacts with each tissue. This vascular system includes arteries, venules and veins and capillaries. Capillaries comprise the smallest segments of the vascular system, known as the microvasculature and have varying properties depending on the requirements of the area they vascularize.
There are three structural classes of capillaries: discontinuous, continuous fenestrated, and continuous non-fenestrated.
- Discontinuous capillaries are found only in the liver and have intercellular gaps which allow for large molecules and cells to be transported between the blood and tissue, supporting metabolism.
- Continuous fenestrated capillaries have small perforations in their cell walls which allows for molecular exchange. This is important in the areas that require frequent exchanges between blood and tissue, such as the filtration of waste products by the kidneys, or absorption of nutrients by the small intestine.
- Continuous non-fenestrated capillaries have a complete plasma membrane with no perforations, allowing only small molecules to pass between their intercellular clefts, such as water or ions.
The microvasculature of the central nervous system
The blood-brain barrier (BBB) is a term used to describe the unique properties of the microvasculature of the central nervous system (CNS). Blood vessels of the CNS are continuous non-fenestrated vessels but have additional distinct properties which tightly govern the movement of small molecules and ions. The BBB is highly selective, allowing only certain substances to travel from the bloodstream to the brain, providing the CNS with protection from pathogens, toxins, and neurochemical imbalance.
Cells of the blood-brain barrier
The interior surface of blood vessels is lined with endothelial cells, which form a one-cell thick layer referred to as the endothelium. Throughout other areas of the body, the endothelium is fenestrated. The endothelial cells of the blood-brain barrier however are securely fused together by tight cell junctions, a class of cellular structure that provides adhesion between neighboring cells, restricting diffusion of solutes between the blood and the brain.
Astrocytes, a type of glial cell in the CNS, perform specialized functions called astrocytic end-feet, a projection from the cell body of the astrocyte to the membrane surrounding the endothelium. Astrocytic end-feet are thought to play a critical role in the formation and regulation of the BBB by interacting with endothelial cells and influencing the signaling to tight cell junctions.
Although primarily to maintain the BBB, astrocytic end-feet may also influence the transient opening of the BBB under certain physiological circumstances. Examples may include the passage of antibodies or cytokines that stimulate cell growth from plasma to the brain.
Blood Brain Barrier, Animation
Dysfunction of the blood-brain barrier
Functional imaging techniques such as functional Magnetic Resonance Imaging (fMRI) and Positron Emission Tomography (PET) and post-mortem analysis of brain samples have identified pathological dysfunction of the blood-brain barrier in many neurological disorders.
Although BBB pathology is typically a functional symptom of a primary neurological disorder, in some diseases including Alzheimer's Disease and Muscular Sclerosis, it has been hypothesized as a cause.
Multiple sclerosis (MS)
Multiple sclerosis is an autoimmune disorder whereby inflammation of the brain and spinal cord disrupts nerve signaling between the brain and body. Although the etiology of MS is unclear and likely to include multiple epigenetic factors, the breakdown of the blood-brain barrier is observed in the early stages of the disease. Recent research suggests that in MS, an abnormal immune response damages the myelin (the protein and lipid-rich substance surrounding cell axons) of the CNS. Myelin-producing cells, known as oligodendrocyte precursor cells (OPCs), however, are unable to cross the BBB to repair areas of damage. Thus, the BBB plays a role in both the initiation and maintenance of the inflammatory disorder.
Hypoxia and cerebral ischemia
Among the different stressors which induce disruption to the blood-brain barrier, hypoxic and ischemic challenges (reduced oxygen and/or reduced glucose delivery to the brain) are acutely injurious to brain function and can trigger the death of neuronal cells within minutes. Cerebral ischemia (stroke) induces severe brain injury and substantive disruption to the BBB.
Although the mechanisms by which hypoxia and ischemia disrupt the BBB remain unclear, oxidative stress is thought to be contributory. Oxidative stress is an imbalance of pro and anti-oxidants resulting in elevated reactive oxygen species (ROS) and may affect the integrity of the endothelium, breaking down the BBB.
Alzheimer’s Disease (AD)
Dysfunction of the blood-brain barrier has been well documented in post-mortem studies of individuals with established AD. However, recent studies which have imaged the brains of people with mild cognitive impairment (MCI) and early Alzheimer’s disease have shown the breakdown of the BBB prior to brain atrophy or dementia, suggesting it occurs at an early stage of the disease. Although the extent of BBB dysfunction and its causal role in Alzheimer’s disease continues to be debated, one theory suggests that BBB leakage caused by aging, illness, or injury could cause an inflammatory response leading to Alzheimer’s disease pathology.
References
- Abbott, N., Rönnbäck, L. & Hansson, E. Astrocyte–endothelial interactions at the blood–brain
- Al Ahmad, A., Gassmann, M., & Ogunshola, O. O. (2012). Involvement of oxidative stress in hypoxia-induced blood-brain barrier breakdown. Microvascular research, 84(2), 222–225. https://doi.org/10.1016/j.mvr.2012.05.008
- Caterina P. Profaci, Roeben N. Munji, Robert S. Pulido, Richard Daneman; The blood–brain barrier in health and disease: Important unanswered questions. J Exp Med 6 April 2020; 217 (4): e20190062. doi: https://doi.org/10.1084/jem.20190062
- Daneman, R., & Prat, A. (2015). The blood-brain barrier. Cold Spring Harbor perspectives in biology, 7(1), a020412. https://doi.org/10.1101/cshperspect.a020412
- Daneman R. (2012). The blood-brain barrier in health and disease. Annals of neurology, 72(5), 648–672. https://doi.org/10.1002/ana.23648
- Griffin, C. T., & Gao, S. (2017). Building discontinuous liver sinusoidal vessels. The Journal of clinical investigation, 127(3), 790–792. https://doi.org/10.1172/JCI92823
Further Reading
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